IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance.
The proinflammatory cytokine TNFalpha is one of the factors that links obesity-derived chronic inflammation with insulin resistance. Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1. It remains elusive that whether the mTOR pathway has a role in TNFalpha-mediated insulin resistance. In the present study, we demonstrated that TNFalpha-IKKbeta-mediated inactivation of TSC1 resulted in increasing phosphorylation of IRS1 serine 307 and serine 636/639, impaired insulin-induced glucose uptake, tyrosine phosphorylation of IRS1, and the association between IRS1 and PI3K p85. Furthermore, a higher expression of pIKKbeta (S181), pTSC1(S511), and pS6(S240/244) was found in livers obtained from both C57BL/6J mice on a high-fat diet and B6.V-Lepob/J mice. Collectively, dysregulation of the TSC1/ TSC2/mTOR signaling pathway by IKKbeta is a common molecular switch for both cancer pathogenesis and diet- and obesity-induced insulin resistance.
Lee
Dung-Fang
DF
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Kuo
Hsu-Ping
HP
Chen
Chun-Te
CT
Wei
Yongkun
Y
Chou
Chao-Kai
CK
Hung
Jen-Yu
JY
Yen
Chia-Jui
CJ
Hung
Mien-Chie
MC
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002908:Chronic Disease; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D051550:I-kappa B Kinase; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C526295:Irs1 protein, mouse; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; C546843:mTOR protein, mouse; C512964:Rps6ka1 protein, mouse; C496562:Ikbkb protein, mouse